02 mothy hkg flt3-inhibitors 22 feb 2013 030213

7/24/2019 02 Mothy Hkg Flt3-Inhibitors 22 Feb 2013 030213

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"FLT3-ITD and FLT3 Inhibitors"FLT3-ITD and FLT3 Inhibitors

in the Setting of Allogeneic Stem Cellin the Setting of Allogeneic Stem Cell

Transplantation for AML"Transplantation for AML"

Pr. Mohamad MOHTY

Head, Clinical Hematology and

Cellular Therapy Dpt.Universit Pierre Marie Curie

H!pital "aint#$ntoine

Paris, %rance


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JMD

T!

T

&a'ao M, (eu'emia )**+ -hitman "P, Cancer es /00) Thiede C, 1lood /00/

2ottaridis PD, 1lood /00/ 3ale 4, 1lood /005 1reiten6uecher %, 1lood /005

%(T7%(T7M#tationsM#tations

FMS-like tyrosine kinase 3

- $ %& of patients 'ith AML

- (igh incidence in AML 'ith

&PM) m#tations )*+&,

t)!%!.,)/!/!,0PM(-$$ )*+-*%&, t)12,)p3/3*,0D42-&UP/)8).%&,

- Associated 'ith inferior prognosis

Allelic ratio )m#t0't, ITD insertion site


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%(T7-ITD - 4egati5e 6rognostic Impact

in the Conte7t of 8ther 9enetic Aberrations

M#lti5ariable Anal:sis on 85erall S#r5i5al

n;32< =C89 =!2++

Total cohort (> p-5al#e

%(T7-ITD !?%2 +?++3

Intermediate-ris@

(> p-5al#e%(T7-ITD ?%* +?++!

Patel 9P, et al. & 4ngl 9 Med. /0)/7++:)0;*#5*.


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6;+?.! 6;+?++3

Donor n;1+

4o-Donor n;!*FS and 8S according to insertion site

2ayser et al., 1lood /00*))8:/75+#*/.


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T:rosine inase Inhibitors

Selecti5it: and 6otenc:

Sta#rosporine Midosta#rin Sorafenib S#nitinib K#iartinib

2araman M-, et al. &ature 1iotechnology /005/+ A)B:)/;#)7/arrin'ar PP, et al. 1lood. /00*))8A)8B:/*58#/**/..


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Sorafenib in >elapsed 6atients 'ith

%(T7-ITD positi5e AML

Metelder et al., (eu'emia /0)/ epu6 05.0?./0)/

6op#lation

n;1% patients )n;13 relapsed0refractor: n; in C>,

T'o cohorts

a, n;2 pts? after allo-(SCT

b, n;31 pts? after intensi5e chemothera:

Treatment Sorafenib starting dose 7 *++ mg

Median d#ration and dosea, .1 da:s )!*-2+*, 1++ mg0d

b, .* da:s )!-.+, *esponse cohort-a cohort-b

CM> . )*&, 3 )


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Sorafenib in >elapsed 6atients after

allo-(SCT 'ith %(T7-ITD positi5e AML

Me*ian treat+ent *,ration (" *ays #1-2(0 *ays)

+e*ian *ose 600 +g*

Metelder et al., (eu'emia /0)/ epu6 05.0?./0)/

.ora/eni treat+ent

Allogenei H.'T

Ti+e to treat+ent /ail,re

n=2$

n=36


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K#iartinib in >elapsed 6atients 'ith

%(T7-ITD positi5e AML

(eEis et al., $"H /0)/ F+;7

6op#lationn;22 patients )relapsed0refractor:,

T'o cohorts

a, n;% pts? after allogeneic (SCT

b, n;.* pts? after intensi5e chemotherap:

Treatment K#iartinib starting dose 2+mg0!3%mg

>esponse cohort-a cohort-b

C>0C>i !* )%1&, 3+ )*!&,

6>0(>0GM> 1 )*&, !. )3&,refractor: % )+&, . )31&,

Median response d#ration !!?3 'ee@s


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.ora/eni Maintenane Terapy /or atients 4it AM5 A/ter Allogenei .te+ 'ell

Transplant )4CT+!32

'o+pletion Date: Dee+er 201%

A *o,le-lin*7 plaeo-ontrolle*7 ran*o+i@e*7 +,lti-enter pase II trial to assess

te e//iay o/ .ora/eni-+aintenane terapy in FLT3-ITD positi9e AM5 in o+plete

e+atologial re+ission a/ter allogeni ste+ ell transplantation ; =#draCT 4#mber

+!+-+!


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Concl#sions

%(T7-ITD is fre/#entl: present in ad#lt AML 'ith

highest incidence in patients aged !< to 1+ :ears

In normal car:ot:pe AML important cooperating gene

m#tations are &PM)-m#t and D&MT7$-m#t

M#tant0'ild t:pe ratio and insertion in the !-sheet are

important prognostic mar@ers in %(T7-ITD positi5e

AML


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Concl#sions

Allo-(SCT in first C> in %(T7-ITD positi5e AML res#lts

in impro5ed o#tcome especiall: in those patientslac@ing a high m#tant0'ild t:pe ratio and0or insertion

in the !-sheet

TIs sho'ed remar@able acti5it: as single agent in

relapsed0refractor: %(T7-ITDpos AML especiall: after

allo-(SCT

Dr#g-Dr#g interactions ma: hea5il: infl#ence TI

metabolism 5ia C:tochrome 6*%+3A*

TIs can bloc@ gl#c#ronidation of dr#gs e?g?

paracetamol 'hich ma: lead to se5er hepatoto7icit:

02 mothy hkg flt3-inhibitors 22 feb 2013 030213

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